a) Field of the Invention
The present invention relates in general to the field of the treatment of psoriasis and related skin disorders, and more particularly to a non-toxic oral and topical formulation that includes a pharmaceutically effective amount of dairy proteins for the treatment of psoriasis and related immune system disorders.
b) Description of the Prior Art
It is not known what causes psoriasis, although there is evidence of a genetic predisposition and an autoimmune etiology. Onset may be triggered by systemic infections such as streptococcus throat, skin injury, vaccinations, and certain oral medications such as steroids. Subsequently, the immune system is thought to induce inflammation and excessive skin cell reproduction, which can be exacerbated by additional factors such as stress and diet.
In normal skin, a cell moves from the basal layer through the granular layer in 4-5 weeks. In psoriatic lesions, the time is decreased 7-10 fold because of a shortened cell cycle time, an increase in the absolute number of cells capable of proliferating, and an increased rate of division. T cell mediated immune responses appear to be responsible for the inflammation and hyperproliferation of keratinocytes. Neutrophils are found in psoriatic lesions, associated with increased levels of plasminogen activators. Psoriatic fibroblasts have increased levels of enzymes involved in collagen synthesis, secondary to expansion of the papillary dermis. Psoriatic plaques comprise HLA-DR positive keratinocytes and Langerhans cells, and activated T cells expressing elevated levels of IL-2 receptors.
The typical lesion of psoriasis is a well-demarcated erythematous plaque, covered by thick, silvery scales. Psoriasis can become so extensive as to cause exfoliative erythroderma, in which the entire epidermal surface is in a state of hyperproliferation. Gluttate psoriasis is a form of the disease following streptococcal pharyngitis, with widely distributed characteristic 1-3 cm lesions. Pustular psoriasis is characterized by numerous sterile pustules of 2-5 mm in diameter, and may lead to an acute, explosive, life-threatening episode of fever, chills, leukocytosis, hypoalbuminemia, and hypocalcemia, demanding immediate, vigorous therapy. Previously stable plaque-type psoriasis can be acutely exacerbated by viral infections, particularly HIV. Psoriasis is also associated with five different forms of psoriatic arthritis, including distal interpharangeal involvement; an asymmetric, oligoarticular pattern; a symmetric polyarthritis; arthritis mutilans; and sacroiliitis and spondylitis.
The inflammation and hyperproliferation of psoriatic tissue is associated with a different histological and antigenic profile than normal skin. A panel of anti-carbohydrate monoclonal antibodies as described in the art, can be used to compare psoriatic tissue with the surrounding dermis. The glycosylation pattern in psoriatic epithelium is changed in two ways: some carbohydrates are expressed at an earlier stage of cell maturation. In addition, certain biosynthetic precursor antigens not expressed in normal skin were found in psoriatic skin.
Classical treatments of psoriasis include calcipotriene (a vitamin D3 derivative), topical coal tar preparations, systemic antimitotic agents such as methotrexate, and retinoids, particularly etretinate.
Extensive psoriasis can be treated by photosensitization with oral 8-methoxypsoralen, followed by ultraviolet A. Corticosteroids are given for psoriatic arthritis and acute attacks of pustular psoriasis. More recently, cyclosporin A has been tested in clinical trials at doses of 3-7 mg/kg with promising results, but associated with the risk of renal toxicity.
Current biotechnology approaches to psoriasis treatment relate to a direct pharmaceutical-mediated attack, either on cell proliferation or on the immune component of the disease. Japanese patent application JP 6145069 describes angiogenesis inhibitors comprising ganglioside GM3 or a GM3 analog as an active agent. At 100 μg/mL, GM3 showed growth of normal human anti-endothelial cells of 4.5.times.104 on day 5, compared with 76.times.104 in controls. U.S. Pat. No. 5,339,977 describes n-deacetyl-lysoganglioside derivatives for use as phospholipase A2 inhibitors for the treatment of proliferative and autoimmune diseases, including various forms of cancer, psoriasis, and rheumatoid arthritis.
An IL-2 fusion toxin has been developed (Seragen, Inc.) that is designed to selectively destroy activated T cells in psoriatic plaques, leaving normal cells alone. The objective is to destroy activated T cells, and thereby clear the psoriasis. A Phase II study has been performed in which test doses of 5, 10, and 15 μg/kg were administered per day. Comparable improvement was observed in patients with moderate to severe psoriasis. However, in order to obtain this response, the compound was administered three days per week for four weeks.
Various formulations containing the compound BCX-34 for psoriasis, cutaneous T cell lymphoma, and HIV infection have been tested WO 95/01355; WO 93/21187; WO 90/10631; U.S. Pat. Nos. 5,008,270, 5,008,265, and 4,985,434). BCX-34 is a small molecule drug that inhibits purine nucleoside phosphorylase, a human enzyme believed to be involved in the proliferation of T cells. An oral formulation is being tested in an ongoing Phase I/II trial. A topical formulation advanced to the Phase III stage for both lymphoma and psoriasis. The Phase III psoriasis study showed only a 14% greater improvement in mean lesion scores in the treated group compared to placebos, which for these studies was not statistically significant.
Several drugs have been designed to treat psoriasis by targeting specific cells, specific cytokines, or specific interactions between ligands and receptors. The main advantage of these biological agents over cyclosporin and methotrexate is the absence of nephrotoxicity and hepatotoxicity, but toxic effects can take years to develop. Candidates for biological therapy will be those who cannot comply with the rigors of a phototherapy regimen or have received too much PUVA and are at risk of hepatotoxicity and nephrotoxicity.
Another product available in the art consist in a chimeric human tumor necrosis factor α monoclonal antibody derived from mouse. It is made of the human constant and mouse variable regions of the IgG antibody. This agent is administered by intravenous infusion over at least 2 h and neutralizes soluble tumor necrosis factor α bound to cell membranes. Results of several case reports attest to the efficacy of this agent in the treatment of psoriasis. Drawbacks of the drug include the need for slow intravenous infusion. A small but real proportion of patients have infusion reactions, including potentially serious reactions such as hypotension, rigors, and allergic reactions. These reactions can often be prevented by slowing down the infusion or pre-treating with antihistamines or, for some conditions, systemic corticosteroids. Neutralizing antibodies can develop, making the treatment less effective. Worse, patients who develop neutralizing antibodies are more likely to develop infusion reactions. One of the greatest concerns is the potential for infection with this tumor necrosis factor α inhibitor.
Alternatively, recombinant tumor necrosis factor α receptor fusion proteins were developed, which consist of two extracellular ligand-binding domains of the human p75 tumor necrosis factor α receptor fused to the Fc portion of human IgG1. These fusion proteins are likely effective for psoriatic arthritis and seems to be safer than cyclosporin or methotrexate with no nephrotoxicity or hepatotoxicity. Non-neutralizing antibodies occur in less than 5% of patients. Antinuclear antibodies and antibodies to double-stranded DNA have been reported, but full cases of systemic lupus erythematosus are rare. Anticardiolipin antibodies also develop but have been attributed to minor concomitant infections. Because this agent is a tumor necrosis factor α inhibitor, concern has been raised about the potential for immunosuppression leading to infection.
Humanized anti-CD11a monoclonal antibody was also developed for the treatment of moderate-to-severe plaque psoriasis and moderate-to-severe rheumatoid arthritis. It is normally administered as a subcutaneous (under the skin) injection, and is designed to inhibit the binding of immune system T-cells to other cell types and targets three key processes in the cascade of events that lead to autoimmune symptoms.
Another family of products is known in the art to prevent T cell activation by blocking the LFA-3/CD-2 pathway through binding to the CD2 receptor. It is an IV/IM administered product. Since this family of products may cause reduction in CD4+ and CD8+ T lymphocyte counts, it may not be appropriate for all individuals.
A fully human fusion protein consisting of a binding site of LFA-3 fused to the Fc portion of IgG1 CD45Ro+ memory T cells, which have a major role in development of psoriasis, maximally express CD2, a natural ligand of LFA-3 has been developed. By binding CD2, it prevents T-cell activation. Moreover, the Fc portion of the molecule engages Fc receptors on macrophages and NK cells, which results in apoptosis of the CD45RO+ T cells.
Another humanized monoclonal antibody to CD11a was developed, which is a component of LFA-1 on T cells and ICAM-1 on antigen-presenting cells that is an important co-stimulatory signal resulting in T-cell activation. ICAM-1 on endothelial cells also interacts with LFA-1 on circulating T cells, a necessary step for migration of T cells into inflamed skin. It can thus interfere with development of psoriasis by blocking T-cell migration into the skin and by preventing T-cell activation. In clinical trials, some patients developed flu-like symptoms including headache, chills, fever, nausea, vomiting, or myalgias. Symptoms arose on the day of injection or the following 2 days. These acute adverse events subsided by the third dose.
Systemic treatment has been used in patients with physically, socially, or economically disabling psoriasis that has not responded to topical treatment. The choices to date have been phototherapy or systemic drug therapy. Generally, systemic treatment has employed phototherapy with Ultraviolet B irradiation, photo chemotherapy which combines the photosensitizing drug methoxsalen with Ultraviolet A phototherapy (PUVA), methotrexate, etretinate, systemic corticosteroids, and cyclosporine. Each of these systemic treatments has variable efficacy and undesired side effects, and some of them are very toxic and present frequent relapses of the disease.
The number of different and sometimes toxic treatments employed for improvement of psoriasis symptoms is testimony to the resistant nature of this disease. Not only is moderate to severe psoriasis resistant to topical treatments, but because of its chronic and recurrent nature, systemic therapy or radiation is often required. The devastating nature of this disease is emphasized by the extent of the side effects that psoriasis sufferers are willing to endure to attain a remission to a disease that they know will recur sooner or later.
Keratinocyte function is regulated via intracellular signaling pathways triggered by growth factors and adhesion molecules. Among them, the EGF family and the TGF-β family are thought to play central roles; they provide dual mode regulation of keratinocytes growth via the proliferation-stimulating effect of EGF and the proliferation-inhibiting effect of TGF-β. TGF-βs exert a wide range of biological effects on keratinocytes, such as growth inhibition, production of extracellular matrix, and synthesis of plasminogen activator and its inhibitor (PAI 1). Among them, growth inhibition is the most prominent.
TGF-β1 and TGF-β2 are synthesized and secreted in human keratinocytes. It seems that TGF-β3 is not a major TGF-β in human keratinocytes growth. Vitamin D3 is a strong inhibitor of keratinocyte growth. The involvement of TGF-β production induced by vitamin D3 increased the expression of TGF-β2 mRNA 4 to 5 fold. In contrast, TGF-β1 mRNA and TGF-β3 mRNA were not increased. Taken together, these data suggest that the intrinsic TGF-βs regulate autonomous growth of human keratinocytes, and have demonstrated that TGF-β antagonized the acanthotic and degenerative effect of TGF-α involved in psoriatic skin, but TGF-β alone did not cause granular layers to appear in the involved psoriatic epidermis, indicating that TGF-β alone cannot normalize the psoriatic condition of the epidermis.
TGF-β is now recognized as a potent growth inhibitor for human keratinocytes. TGF-β2, which was found through the normal human epidermis, was decreased in the psoriatic epidermis. Since TGF-β is a strong growth inhibitor for human keratinocytes, this result indicates the possibility that the decrease of TGF-β2 is involved in the pathogenesis of psoriasis. Therefore, the decrease in TGF-β2 in psoriasis epidermis may induce the accelerated proliferation of keratinocytes and result in epidermal hyperplasia. TGF-β is also a potent immunosuppressive agent. So the decrease of TGF-β2 may permit propagation of an immune/inflammatory reaction in the dermis and epidermis of involved psoriasis. It has been supposed that an immune-activation triggers the growth activation of epidermal keratinocytes in psoriasis. In terms of growth regulation of keratinocytes, an involvement of two groups of growth factors and cytokines, proliferation-stimulating growth factors and proliferation-inhibitory growth factors, has been reported. EGF family growth factors (TGF-α, amphiregulin and HB-EGF), KGF and IL-6 are well known as proliferation-stimulating growth factors. TGF-β family growth factors are the major proliferation-inhibitory growth factors. The increase of TGF-α, amphiregulin and IL-6 was found in psoriasis. Autocrine- or cross-induction of EGF family growth factors may play an important role in epidermal hyperplasia.
One important group of growth factors involved in psoriasis mechanisms are the dermally-derived insulin-like growth factors (IGFs), which support keratinocyte proliferation. In particular, IGF-I and IGF-II are ubiquitous peptides each with potent mitogenic effects on a broad range of cells. Molecules of the IGF type are also known as “progression factors” promoting “competent” cells through DNA synthesis. The IGFs act through a common receptor known as the Type I or IGF-I receptor, which is tyrosine kinase linked. They are synthesized in mesenchymal tissues, including the dermis, and act on adjacent cells of mesodermal, endodermal or ectodermal origin. The regulation of their synthesis involves growth hormone (GH) in the liver, but is poorly defined in most tissues.
Particular proteins, referred to as IGF binding proteins (IGFBPs), appear to be involved in autocrine/paracrine regulation of tissue IGF availability. Six IGFBPs have so far been identified. The exact effects of the IGFBPs is not clear and observed effects in vitro have been inhibitory or stimulatory depending on the experimental method employed. There is some evidence, however, that certain IGFBPs are involved in targeting IGF-I to its cell surface receptor.
Skin, comprising epidermis and underlying dermis, has GH receptors on dermal fibroblasts. Fibroblasts synthesize IGF-I as well as IGFBPs-3, -4, -5 and -6, which may be involved in targeting IGF-I to adjacent cells as well as to the overlaying epidermis. The major epidermal cell type, the keratinocyte, does not synthesize IGF-I, but possesses IGF-I receptors and is responsive to IGF-I.
U.S. Pat. No. 7,141,262 issued to Maubois et al. discloses a method for obtaining a TGF-β enriched protein fraction in activated form. However, in contrast to the present invention, this document discloses a method and a composition that contains a majority (45 to 80%) of α-lactalbumin and which intends to limit the amount of β-lactoglobulin as much as possible (less than 11%).
Considering the state of the art described above, there is still a significant need for an effective psoriasis treatment that avoids the disadvantages associated with the currently available topical or systemic treatments.